Disrupted Binding of Cystathionine γ-Lyase to p53 Promotes Endothelial Senescence

作者：Jiong Hu, Matthias S. Leisegang, Mario Looso, Maria-Kyriaki Drekolia, Janina Wittig, Janina Mettner, Christina Karantanou, Anastasia Kyselova, Gabrijela Dumbović, Xiaoming Li, Yuanyuan Li, Stefan Günther, David John, Mauro Siragusa, Sven Zukunft, James A. Oo, Ilka Wittig, Susanne Hille, Andreas Weigert, Stefan Knapp, Ralf P. Brandes, Oliver J. Müller, Andreas Papapetropoulos, Fragiska Sigala, Gergana Dobreva, Baktybek Kojonazarov, Ingrid Fleming, Sofia‐Iris Bibli · 发表于：Circulation Research · 年份：2023 · DOI：10.1161/circresaha.123.323084 · 被引用次数：27 · 研究领域：Sulfur Compounds in Biology、Folate and B Vitamins Research、Nitric Oxide and Endothelin Effects

BACKGROUND: Advanced age is unequivocally linked to the development of cardiovascular disease; however, the mechanisms resulting in reduced endothelial cell regeneration remain poorly understood. Here, we investigated novel mechanisms involved in endothelial cell senescence that impact endothelial cell transcription and vascular repair after injury. METHODS: Native endothelial cells were isolated from young (20±3.4 years) and aged (80±2.3 years) individuals and subjected to molecular analyses to assess global transcriptional and metabolic changes. In vitro studies were conducted using primary human and murine endothelial cells. A murine aortic re-endothelialization model was used to examine endothelial cell regenerative capacity in vivo. RESULTS: RNA sequencing of native endothelial cells revealed that aging resulted in p53-mediated reprogramming to express senescence-associated genes and suppress glycolysis. Reduced glucose uptake and ATP contributed to attenuated assembly of the telomerase complex, which was required for endothelial cell proliferation. Enhanced p53 activity in aging was linked to its acetylation on K120 due to enhanced activity of the acetyltransferase MOZ (monocytic leukemic zinc finger). Mechanistically, p53 acetylation and translocation were, at least partially, attributed to the loss of the vasoprotective enzyme, CSE (cystathionine γ-lyase). CSE physically anchored p53 in the cytosol to prevent its nuclear translocation and CSE absence inhibited AKT (Pr...